WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 6 :
C12Q 1/0O, G01N 27/327, C12Q 1/54
Al
(11) International Publication Number: WO 99A3099
(43) International Publication Date: 18 March 1999 (18.03.99)
(21) International Application Number: PCT/US98/18216
(22) International Filing Date: 2 September 1998 (02.09.98)
(30) Priority Data:
08/924,266
5 September 1997 (05.09.97) US
(71) Applicant: ABBOTT LABORATORIES [US/US]; CHAD
0377/AP6D-2, 100 Abbott Park Road, Abbott Park, IL
60064-3500 (US).
(72) Inventors: HUGHES, Graham, J.; 23 New Cross Road, Head-
ington, Oxford OX3 8LP (GB). CHAMBERS, Geoffrey, R.;
32 Elgood Avenue, Northwood, Middlesex HA6 3QS (GB).
(74) Agents: POPE, Lawrence, C. et al.; Abbott Laboratories,
CHAD 0377/AP6D-2, 100 Abbott Park Road, Abbott Park,
IL 60064-3500 (US).
(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ,
TM, TR, TT, UA, UG, UZ, VN, YUTZVV-, AM*) patent
(GH, GM. KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent
(AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent
(AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT,
LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF. CG, CI,
CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
Published
With international starch report.
(54) Title: ELECTROCHEMICAL SENSOR HAVING EQUALIZED ELECTRODE AREAS
(57) Abstract
An improved electrochemical sensor strip is disclosed. In a multiple
electrode sensor strip, equalization of electrode networking areas, as well
as working areas, enhances the overall precision and accuracy of the
measurements made using the sensor strip. The beneficial effect of area
equalization is most pronounced at relatively low glucose concentrations.
In the present invention, the exactness and reproducibility of electrode area
equalization is improved by avoidance of overlap between the electrodes
and a dielectric coating that defines an electrode exposure area.
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
AL
Albania
ES
Spain
LS
Lesotho
SI
Slovenia
AM
Armenia
FI
Finland
LT
T Jthuania
SK
Slovakia
AT
Austria
FR
Prance
LU
Luxembourg
SN
Senegal
AU
Australia
GA
Gabon
LV
Latvia
sz
Swaziland
AZ
Azerbaijan
GB
United Kingdom
MC
Monaco
TD
Chad
BA
Bosnia and Herzegovina
GE
Georgia
MD
Republic of Moldova
TG
Togo
BB
Barbados
GH
Ghana
MG
Madagascar
TJ
Tajikistan
BB
Belgium
GN
Guinea
MK
The former Yugoslav
TM
Turkmenistan
BF
Buridna Faso
GR
Greece
Republic of Macedonia
TR
Turkey
BG
Bulgaria
HU
Hungary
ML
Mali
TT
Trinidad and Tobago
BJ
Benin
IE
Ire land
MN
Mongolia
UA
Ukraine
BR
Brazil
IL
Israel
MR
Mauritania
UG
Uganda
BY
Belarus
IS
Iceland
MW
Malawi
US
United States of America
CA
Canada
IT
Italy
MX
Mexico
uz
Uzbekistan
CF
Central African Republic
JP
Japan
NE
Niger
VN
Viet Nam
CG
Congo
KE
Kenya
NL
Netherlands
YU
Yugoslavia
CH
Switzerland
KG
Kyrgyzstan
NO
Norway
ZW
Zimbabwe
a
Cete d'Tvoire
KF
Democratic People's
NZ
New Zealand
CM
Cameroon
Republic of Korea
PL
Poland
CN
China
KR
Republic of Korea
PT
CU
Cuba
KZ
Kazakstan
RO
Romania
CZ
Czech Republic
LC
Saint Lucia
RU
Russian Federation
DB
Germany
U
SD
Sudan
DK
BE
Denmark
LK
LR
Sri Lanka
Liberia
SB
SG
Sweden
Singapore
WO 99/13099
PCT/US98/18216
1
ELECTROCHEMICAL SENSOR HAVING EQUALIZED ELECTRODE AREAS
Field of the Invention
- - The invention relates to electrochemical sensors, biomedical testing, and blood analysis.
Background of the Invention " ■ ~
Electrochemical assays for determining the concentration of enzymes or their substrates
in complex liquid mixtures have been developed. For example, electrochemical sensor .
strips have been developed for the detection of blood glucose levels. Electrochemical
sensor strips generally include an electrochemical cell in which there is a working electrode
and a reference electrodes. The potential of the working electrode typically is kept at a
constant value relative to that of the reference electrode.
Electrochemical sensor strips are also used in the chemical industry and food industry, to
analyze complex mixtures. Electrochemical sensors are useful in biomedical research,
where they can function as invasive probes, and for external testing (i.e., testing of blood
obtained by a needle and syringe, or a lance).
Typical electrochemical sensors for blood analysis measure the amount of analyte in a
blood sample by using a working electrode coated with a layer containing an enzyme and a
redox mediator and a reference electrode. When the electrodes contact a liquid sample
containing a species for which the enzyme is catalytically active, the redox mediator
transfers electrons in the catalyzed reaction. When a voltage is applied across the electrodes,
a response current results from the reduction or oxidation of the redox mediator at the
electrodes. The response current is proportional to the concentration of the substrate. Some
sensors include a dummy electrode coated with a layer containing the redox mediator but
lacking the enzyme. The response current at the dummy electrode represents a background
response of the electrode in contact with the sample. A corrected response is derived by
subtracting the response of the dummy electrode from the response of the working electrode.
This dummy subtraction process substantially eliminates background interferences, thereby
improving the signal-to-noise ratio in the electrode system.
Summary of the Invention
It has been discovered that equalizing the exposed areas of electrode regions having no
electrochemical reaction components by which to generate a catalytic current increases the
accuracy and precision of analyte concentration measurements. This result was unexpected.
According to conventional electrochemical theory, the magnitude of current from such areas
WO 99/13099
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2
should be negligible relative to the current generated at the working areas of the electrodes.
Based on this discovery, the invention features an improved electrode strip for use in an
electrochemical sensor for measuring an analyte in a sample. The electrode strip includes an
electrode support, which has a first support edge and a second support edge, and an electrode
arrangement on the support. The electrode arrangement includes a working electrode," a" ~~ "
dummy electrode, and a reference electrode. The working electrode includes a working
area, which contains assay reaction components, including an enzyme and a redox mediator.
The working electrode also includes an extension, which is substantially free of the enzyme
and redox mediator, and an outside edge. The dummy electrode includes a working area,
which contains assay reaction components, except the enzyme. The dummy electrode also
includes an extension, which is substantially free of assay reaction components, and an
outside edge. The reference electrode has a working area-facing side and an extension-
facing side. The working area extension is located between the reference electrode and the
first support edge. The dummy electrode extension is located between the reference
electrode and the second support edge. The electrode strip includes a dielectric coating,
which covers a portion of the support. The covered portion of the support includes an area
located between the working electrode extension and the first support edge, and an area
located between the dummy electrode extension and the second support edge, and the
dielectric coating covers no portion of the outside edge of the working electrode or the
outside edge of the dummy electrode.
Preferably, the dielectric coating surrounds the electrode arrangement in which the
working electrode and the dummy electrode have equal areas. Preferably, each electrode is a
printed electrode. Preferably, the enzyme is an enzyme that reacts with glucose, for
example, glucose oxidase or glucose dehydrogenase. The redox mediator can be any
electrochemically active compound that accepts or donates an electron to an enzyme. Redox
mediators include ferrocene, ferrocene derivatives, ferricyanide, and osmium complexes.
Unless otherwise defined, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art to which this invention
belongs. In case of conflict, the present application, including definitions will control. All
publications, patent applications, patents, and other references mentioned herein are
incorporated by reference.
Although methods and materials similar or equivalent to those described herein can be
used, in the practice or testing of the present invention, the preferred methods and materials
WO 99/13099
PCT/US98/18216
3 :
are described below. The materials, methods, and examples are illustrative only and not
intended to be limiting.
Other features and advantages of the invention will be apparent from the detailed
description, and from the claims.
Brief Description of the Drawings ■ ~
Fig. 1 is a top view of the electrode region of a prior art electrode sensor strip.
Fig. 2 is atop view of a preferred embodiment of an electrode strip according to the.
present invention.
Fig. 3 is an exploded view of an electrode strip according to one embodiment of the
invention. ./
Fig. 4 is a perspective view of the assembled strip shown in Fig. 3.
Description of the Preferred Embodiments
In a multiple electrode sensor strip, equalization of electrode nonworking areas, as well
as working areas, enhances the overall precision and accuracy of the measurements made
using the sensor strip. The beneficial effect of area equalization is most pronounced at
relatively low glucose concentrations. In the present invention, the exactness and
reproducibility of electrode area equalization is improved by avoidance of overlap between
the electrodes and a dielectric coating that defines an electrode exposure area.
The invention is illustrated by comparison of Figs. 1 and 2, which depict a prior art
electrode strip and an electrode strip of the invention, respectively. Referring to Fig. I, the
electrode strip 10 has three printed tracks of electrically conducting carbon ink 11a, lib,
1 lc. A dielectric coating 12 partially covers the electrode strip 10 and defines an open area
13, which includes an electrode arrangement 19 and a sample loading area 20. Each printed
track of electrically conducting carbon ink 1 la, 1 lb, 1 lc terminates in an electrode, in the
open area 13. One track 1 1 a terminates in a working electrode 14. A second track 1 lb
terminates in a dummy electrode 14a. A third track terminates in a reference electrode 16.
The working electrode 14 includes a working area 17, which contains components of an
analyte assay reaction, including glucose oxidase and a ferrocene redox mediator. The
working electrode also includes an extension 1 8, which is a non-working area, i.e., it does
not contain any assay reaction components.
The dummy electrode includes 14a a working area 17a, which contains components of
the assay assay reaction, except the enzyme, glucose oxidase. The dummy electrode also
includes an extension 18a, which is a non-working area, i.e., it does not contain any assay
WO 99/13099
PCT/US98/18216
4
reaction components, the geometry of the dummy electrode 14a forms a mirror image of
the working electrode 14.
The reference electrode 16 is situated so that one side faces the working areas 17, 17a,
-one side faces the working electrode extension 18, and one side faces the dummy electrode
extension 18a.
In the prior art electrode depicted in Fig. 1, dielectric coating 12 covers a portion of the
working electrode 14 and dummy electrode 14a, thereby forming a pair of small overlap
regions 21, 21a.
Referring to Fig. 2, the electrode strip 10 has three printed tracks of electrically
conducting carbon ink 1 la, 1 lb, 1 lc. A dielectric coating 12 partially covers the electrode
strip 10 and defines an open area 13, which includes an electrode arrangement 19 and a
sample loading area 20. Each printed track of electrically conducting carbon ink 1 la, 1 lb,
1 1 c terminates in an electrode, in the open area 1 3. One track 1 1 a terminates in a working
electrode 14. A second track 1 lb terminates in a dummy electrode 1 5. A third track
terminates in a reference electrode 1 6.
The working electrode 1 4 includes a working area 1 7, which contains components of an
analyte assay reaction, including glucose oxidase and a ferrocene redox mediator. .The
working electrode also includes an extension 1 8, which is a non-working area, i.e., it does
not contain any assay reaction components.
The dummy electrode includes 14a a working area 17a, which contains components of
the assay assay reaction, except the enzyme, glucose oxidase. The dummy electrode also
includes an extension 18a, which is a non-working area, i.e., it does not contain any assay
reaction components. The geometry of the dummy electrode 1 4a forms a mirror image of
the working electrode 14.
The reference electrode 1 6 is situated so that one side faces the working areas 17, 17a,
one side faces the working electrode extension48, and one side faces the dummy electrode
extension 18a.
In the electrode depicted in Fig. 2, the dielectric coating 12 extends along the electrode
support edges 22,22a. However, the width of the open area 13 is greater than the width of
the electrode arrangement 19. This creates a gap between the outside edges of the working
and electrodes, and the surrounding dielectric coating 12. Therefore, the dielectric coating
12 covers no portion of the outside edge of the working electrode 14 or the outside edge of
the dummy electrode 14a. The overlap regions 21, 21a, which are present in the prior art
WO 99/13099
PCT/US98/18216
5
electrode strip 10 depicted in Fig. 1, are absent from the electrode strip 10 depicted in
Fig. 2.
A gap can be created between the outside edges of the electrodes and the surrounding
dielectric coating by narrowing the electrodes, or by widening the open area, or both. The
5 extent of electrode narrowing is limited, in part, by the overall resistance of the electrode " *
system and printing tolerances.
As the width of the electrode arrangement 19 and the width of the open area 13 are made
closer, imperfect registration of electrode strip layers can cause the dielectric coating 12
inadvertently to overlap an outside edge 23, 23a of the working electrode 14 or the dummy
10 electrode 14a. Preferably, the difference„between electrode arrangement 19 width and open
area 13 width is great enough to accomodate layer registration tolerances in a manufacturing
process without any overlap of dielectric coating 12 onto electrode edges.
Preferably, the dielectric coating is bonded securely to the electrode support, mesh
layers, and to an electrode strip cover layer (e.g., polyester tape). Preferably, the dielectric
15 layer is hydrophobic. This enhances its ability to confine an aqueous sample to the electrode
area. Preferred materials for use as the dielectric coating are POLYPLAST? and
SERICARD? (Sericol Ltd., Broadstairs, Kent, UK), with SERICARD? being more
preferred.
The working electrode working area 17 is formed from an ink that includes an enzyme, a
20 redox mediator, and a filler. The dummy electrode working area 17a is formed from an ink
that includes the redox mediator and filler, but does not include the enzyme. The respective
inks can be applied to the carbon tracks 1 la, 1 lb by printing, to form discrete working areas
17, 17a When the analyte to be measured is blood glucose, the enzyme is preferably
glucose oxidase, and the redox mediator is a ferrocene derivative.
25 Referring to Fig. 3, the various layers that make up the electrode strip are layed down on
an electrode support 36. The electrode support is typically a plastic material such as PVC,
polycarbonate, or polyester. Three printed tracks of electrically conducting carbon ink 1 la,
1 lb, 11c formed on the electrode support 36. Silver/silver chloride tracks 35a, 35b, 36c are
then overlayed onto the carbon ink tracks 1 la, 1 lb, 1 fc.
30 Referring to Fig. 3, two surfactant coated mesh layers 30, 3 1 overlay the electrode
arrangement 19. The mesh layers protect the printed components from physical damage.
They also facilitate wetting of the electrodes by the aqueous sample. Preferably, the mesh
layers extend over the entire sample path, between and including, the sample loading area 20
A
WO 99/13099
PCT/US98/18216
6
and the electrode arrangement 19. Finely woven nylon is suitable for the mesh layers.
Alternatively, any woven or non-woven material can be used. For a detailed discussion of
the mesh layers see Carter et al., U.S. Patent No. 5,628,890, which is herein incorporated by
reference.
If the mesh material is hydrophobic (e.g., nylon or polyester), it is coated with" a
surfactant. If a hydrophilic mesh is used, the surfactant coating can be omitted.
Hydrophilicity of the mesh allows the sample to wick along the mesh layer to the
electrodes. The wicking properties of the mesh.can be controlled by changing the type or
amount of surfactant on the mesh material. Various surfactants are suitable for coating the
mesh material. A preferred surfactant is FC 170C FLUORAD 7 fluorochemical surfactant
(3M, St. Paul, MN). FLUORAD 7 is a solution of a fluoroaliphatic oxyethylene adduct,
lower polyethylene glycols, 1 ,4-dioxane, and water.
The preferred surfactant loading will vary depending on the type of mesh and surfactant
used and the sample to be analyzed. It can be determined empirically by observing flow of
the sample through the mesh with different levels of surfactant. If two mesh layers are used,
the second (upper) mesh layer preferably is hydrophilic, but not more hydrophilic than the
first (lower) mesh layer. Accordingly, the first mesh layer can have a greater load of
surfactant than the second mesh layer. With regard to the first mesh layer, suitable
surfactant loading for most applications is about 15-20 ?g/mg of mesh (i.e., about 1.0
percent w/v). With regard to the second mesh layer, suitable surfactant loading for most
applications is about 1-10 ?g/mg of mesh.
The mesh layers 30, 31 are held in place by a dielectric coating 12, which impregnates
the periphery of the mesh layers 30, 3 1 . The dielectric coating 12 can be applied by screen
printing. The dielectric coating 12 covers no portion of the electrode arrangement 19.
Preferably, the dielectric coating is hydrophobic, so that it efficiently confines the sample.
Preferably, the hydrophobic dielectric coating is POLYPLAST 7 (Sericol Ltd., Bro&dstairs,
Kent, UK). More preferably, it is SERICARD 7 (Sericol).
The uppermost layer on the electrode strip is a cover layer 32. Preferably, the cover
layer is substantially impermeable. A suitable material for formation of the cover layer 32 is
a flexible polyester tape.
The cover layer 32 defines an upper boundary of the electrochemical cell volume, and
thus, the cover layer 32 determines the maximum depth of the aqueous sample. The cover
layer 32 fixes the upper boundary of the cell volume at a predetermined height, which
WO 99/13099
PCT/US98/18216
7
depends on the thickness of the mesh layers 30, 3 1 . The cell height, and thus maximum
sample depth, is selected to ensure a suitably high solution resistance.
The cover layer 32 has an aperture 33 for sample access to the underlying mesh layers
3-0 r 31. The aperture 33 is located over the sample loading area 20, which is adjacent to the
upstream ends of the working electrode 14 and dummy electrode 14a; The aperture 33 "caff"
be of any suitable size large enough to allow sufficient volume of sample to pass through to
the mesh layers 30, 31 . It should not be so large as to expose any portion of the electrode
arrangement 19. The aperture 33 can be formed in the cover layer 32 by any suitable
method, e.g., die punching.
Cover layer 32 is peripherally affixed to the strip by means of a suitable adhesive. The
cover layer 32 is not affixed in the area of the electrode arrangement 19, the sample loading
area 20, or the area therebetween. Preferably, the cover layer 32 is affixed by means of a hot
melt adhesive. The hot melt adhesive typically has a coating weight between 10 and 50
g/m 2 , preferably from 20 to 30 g/m 2 . Pressure sensitive adhesives or other suitable
adhesives can also be used. When a heat sensitive dielectric coating 12 is used, e.g.,
SERICARD 7 , heat welding of the coyer layer 32 should be carried out in a manner that does
not damage the dielectric coating 12.
Optionally, the upper surface of the cover layer 32 can be coated with a layer of silicone
or other hydrophobic coating. This helps to drive the applied sample onto the hydrophlic
mesh layers 30, 31 at the sample loading area 20, thus facilitating the application of small
volumes.
Referring to Fig. 4, an electrode strip 10 of the invention is connected, via electrode
contacts 34, to a compatible meter (not shown), after a sample is placed in aperture 33.
The following examples are intended to be illustrative and not limiting of the invention.
Example 1 - Spiked Venous Blood Testing
Eleven batches of electrode strips essentially as shown in Fig. 2 were constructed. In
addition, a batch of prior art control strips as shown in Fig. 1 , were constructed.
Samples of venous blood were collected in four studies and spiked with various
concentrations of glucose. Small volumes of each samples were applied to the target area of
the sample and control strips and allowed to cover the working and reference electrodes.
The responses of the strips to the glucose concentration in the blood were measured after a
steady state response was achieved, using an appropriate meter.
The average calibration results for the eleven batches were calculated and are listed in
WO 99/13099
PCT/US98/18216
8
Table 1 . The data include the standard deviations of the results ("S.D.") and the coefficients
of variation ("CV").
Table 1
Glucose
Mean
Pooled S.D.
cv (%;
Level
(mM)
(mM)
1
2.6
0.16
6.1
2
5.1
0.27
5.3
3
9.9
0.44
4.4
4
14.3
0.64
4.5
For comparison, the average precision results for the control batch are listed in
Table 2. The standard deviations and coefficients of variation were consistently higher in the
control strips.
Table 2
Glucose Pooled S.D. CV (%)
Level_ Mean (mM)
(mM)
1 2.7 0.28 10.2
2 5.1 0.34 6.7
3 10.1 0.52 5.1
4 15.1 0.71 4.7
Example 2 - Control Solution Testing
A standard precision test using 96 replicate measurements of an aqueous solution
with a glucose concentration of 2.0 mM was carried out on eleven batches of electrodes of this
invention. The results were compared to results from a corresponding test carried out on control
(prior art) electrode batches. The results are shown in Table 3.
Table 3
_ Mean
Response SD %CV
(mM)
Test Batches 2.4 0.14 5.8
Control Batches 2.3 0.25 10.87
Other embodiments are within the following claims.
WO 99/13099
PCT/US98/18216
9
Claims
We claim:
1 . An electrode strip for use in an electrochemical sensor for measuring an analyte in an
aqueous sample, comprising:
(a) , an electrode support comprising a first support edge and a second support edge; ~
(b) an electrode arrangement on said support, comprising a working electrode, a dummy
electrode, and a reference electrode, wherein:
(1) said working electrode comprises:
(1) an outside edge;
(ii) a working area comprising an enzyme and a redox mediator, and /
(iii) an extension substantially free of said enzyme and said redox mediator;
(2) said dummy electrode comprises:
(i) an outside edge;
(ii) a working area comprising a redox mediator and being substantially free of said
enzyme, and
(iii) an extension substantially free of said enzyme and said redox mediator;
(3) said reference electrode comprises a working area-facing side and
an extension-facing side; and
(4) said working electrode extension is located between said reference electrode and said
first support edge, and said dummy electrode extension is located between said reference
electrode and said second support edge; and
(5) the area of said working electrode extension and the area of said dummy electrode
extension are equal; and
(c) a dielectric coating, wherein: said dielectric coating covers a portion of said support,
which portion is located between said working electrode extension and said first support
edge, and said dummy electrode extension and said second support edge; and said dielectric
coating covers no portion of said outside edge of said working electrode or said outside edge
of said dummy electrode.
2. The electrode strip of claim 1, wherein said dielectric coating surrounds said
electrode arrangement
3. The electrode strip of claim 1 , wherein each electrode is a printed electrode.
4. The electrode strip of claim 1, wherein said enzyme is glucose oxidase and said redox
mediator a ferrocene.
WO 99/13099
PCT/US98/18216
PRIOR ART
FIG. 1
FIG. 2
INTERNATIONAL SEARCH REPORT
tnte. onai Application No
PCT/US 98/18216
A. CLASSIFICATION OF SUBJECT MATTER
IPC 6 C12Q1/00 G01N27/327 C12Q1/54
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC 6 C12Q G01N
Documentation searched other than minlmumdocumentatlon to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category * Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
US 5 628 890 A (CARTER NIGEL F ET AL)
13 May 1997
see the whole document
WO 91 09139 A (B0EHRIN6ER MANNHEIM CORP)
27. June 1991
see page 3, line 11 - page 4, line 23
US 5 512 159 A (YOSHI0KA T0SHIHIK0 ET AO
30 April 1996
see abstract
WO 97 10356 A (CYGNUS THERAPEUTIC SYSTEMS)
20 March 1997
see the whole document
1-4
□
Further documents are fisted In the continuation of box C.
ID
Patent family members are Hated in annex,
* Special categories of cited documents :
*A* document defining the general state of the art which is not
considered to be of particular relevance
"E" earlier document but pubBshed on or after the international
filing date
"V document which may throw doubts on priority dalm(8) or
which is cited to establish the publication date of another
citation or other special reason (as specified) .
"O" document referring to an oral disclosure, use, exhibition or
other means
T" document published prior to the international h'Bng date but
later than the priority date claimed
T" tater document published after the international fling date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention
"X" document of particular relevance: the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document Is taken atone
"Y" document of particular relevance: the claimed invention
cannot be considered to Involve an inventive step when the
document is combined wfth one or more other such docu-
ments, such combination being obvious to a person skilled
in the art
document member of the same patent family
Oate of the actual completion of the international search
4 November 1998
Date of mailing of the International search report
16/11/1998
and mailing address of the ISA
European Patent Office, P.B. 5818 Patentlaan2
NL - 2280 HV Rljswijk
Tel. (+31-70) 340-2040. Tx. 31 851 epo rt.
Fax: (+31-70) 340-3016
Authorized officer
Moreno, C
Form PCT/1S A/210 (second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
Information on patent family members
Inte onal Application No
PCT/US 98/18216
Patent document
cited in search report
Publication
date
Patent family
member(s)
Publication
US 5628890
13-05-1997
WO 9109139
27-06-1991
CA
2159553 A
30-03-1997
JP
9222411 A
26-08-1997
AT
124990 T
15-07-1995
AU
634863 B
04-03-1993
AU '
7171691 A
18-07-1991
CA
2069946 A
16-06-1991
0E
69020908 0 '
17-0B-1995 -
0E
69020908 T
15-02-1996
EP
0505494 A
30-09-1992
ES
2075955 T
16-10-1995
US
5508171 A
16-04-1996
US
5288636 A
22-02-1994
US 5512159
A
30-04-1996
JP
CA
5196595 A
2068475 A,C
06-08-1993
22-07-1993
WO 9710356
A
. 20-03-1997
US
5735273 A
07-04-1998
AU
6497396 A
01-04-1997
CA
2229509 A
20-03-1997
Form PCT/ISA/210 (pa tint famiy unu) (July 1982)
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